SYNTHESIS AND ANALYSIS
The Synthesis and Test of Hypotheses (SynTHy) tool was introduced in the 1.0 release of the encyclopedia. It facilitated the building of advanced search queries in an explorative manner by visualizing the genomic background distribution of numeric data fields and provided real-time visualization of the sets and intersections defined by compound queries in the form of a Venn diagram. In the 2.0 release, this tool has been updated to be able to perform search and analysis on the non-coding genomic elements in the database. In addition, the tool can perform additional statistical tests on the sets defined by the Venn diagram, such as chi-squared tests of independence and t-tests of dependent variables (Figure 2).
Non-coding genetic elements and associations
Enhancer-TSS associations, differential tissue and cell-type enhancer expression were
downloaded from FANTOM531 SlideShare (http://enhancer.binf.ku.dk/presets/). Non-redundant repetitive element annotations were downloaded from Dfam database of repetitive DNA
families32, version 2.0 data release
(http://www.dfam.org/web_download/Release/Dfam_2.0/hg38_dfam.nrph.hits.gz). The genomic elements described by these data were loaded into ElasticSearch using the tools in the
Genestation Search Engine Toolkit (Chapter IV).
Sequence Variation Data
Sequence variation data was compiled from the 1000 Genomes Project Phase 3 dataset34 and dbSNP build 151. Evolutionary metrics were calculated from the 1000 Genomes data using . VCFtools38. Functional associations were downloaded from the GWAS Catalog v1.0 and PheWAS catalog v1.0 releases. Single tissue cis-eQTL data was downloaded from the GTEx Project version 7 data (https://gtexportal.org/home/datasets). These variants and their
associations were loaded into ElasticSearch using the tools in the Genestation Search Engine Toolkit (Chapter IV).
REFERENCES
1. Wagner, G. P., Kin, K., Muglia, L. & Pavlicev, M. Evolution of mammalian pregnancy and the origin of the decidual stromal cell. Int. J. Dev. Biol. 58, 117–126 (2014).
2. Lynch, V. J. et al. Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy. Cell Rep. 10, 551–561 (2015).
3. Brown, E. A., Ruvolo, M. & Sabeti, P. C. Many ways to die, one way to arrive: how selection
acts through pregnancy. Trends Genet. 29, 585–592 (2013).
4. Wittman, A. B. & Wall, L. L. The evolutionary origins of obstructed labor: bipedalism, encephalization, and the human obstetric dilemma. Obstet. Gynecol. Surv. 62, 739–748 (2007).
5. Romero, R., Dey, S. K. & Fisher, S. J. Preterm labor: one syndrome, many causes. Science 345, 760–765 (2014).
6. Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Preterm Birth: Causes, Consequences, and Prevention. (National Academies Press (US), 2010).
7. Smith, V., Devane, D., Begley, C. M., Clarke, M. & Higgins, S. A systematic review and quality assessment of systematic reviews of randomised trials of interventions for preventing and treating preterm birth. Eur. J. Obstet. Gynecol. Reprod. Biol. 142, 3–11 (2009).
8. Bezold, K. Y., Karjalainen, M. K., Hallman, M., Teramo, K. & Muglia, L. J. The genomics of preterm birth: from animal models to human studies. Genome Med. 5, 34 (2013).
9. Swaggart, K. A., Pavlicev, M. & Muglia, L. J. Genomics of preterm birth. Cold Spring Harb.
Perspect. Med. 5, a023127 (2015).
10. Monangi, N. K., Brockway, H. M., House, M., Zhang, G. & Muglia, L. J. The genetics of preterm birth: Progress and promise. Semin. Perinatol. 39, 574–583 (2015).
11. Goldenberg, R. L., Culhane, J. F., Iams, J. D. & Romero, R. Epidemiology and causes of preterm birth. Lancet 371, 75–84 (2008).
12. Winkvist, A., Mogren, I. & Högberg, U. Familial patterns in birth characteristics: impact on individual and population risks. Int. J. Epidemiol. 27, 248–254 (1998).
13. Porter, T. F., Fraser, A. M., Hunter, C. Y., Ward, R. H. & Varner, M. W. The risk of preterm birth across generations. Obstet. Gynecol. 90, 63–67 (1997).
14. Boyd, H. A. et al. Maternal contributions to preterm delivery. Am. J. Epidemiol. 170, 1358–
1364 (2009).
15. Kim, M. et al. GEneSTATION 1.0: a synthetic resource of diverse evolutionary and functional genomic data for studying the evolution of pregnancy-associated tissues and phenotypes. Nucleic Acids Res. 44, D908–16 (2016).
16. Jones, K. E. et al. PanTHERIA: a species-level database of life history, ecology, and geography of extant and recently extinct mammals. Ecology 90, 2648–2648 (2009).
17. Smith, R. J. & Jungers, W. L. Body mass in comparative primatology. J. Hum. Evol. 32,
523–559 (1997).
18. Dobbing, J. Vulnerable Periods in Developing Brain. in Brain, Behaviour, and Iron in the Infant Diet 1–17 (1990).
19. Hradecký, P. & Mossman, H. W. Vertebrate Fetal Membranes: Comparative Ontogeny and Morphology; Evolution; Phylogenetic significance; Basic Functions; Research
Opportunities. The Journal of Zoo Animal Medicine 18, 55 (1987).
20. Müller, D. W. H. et al. Dichotomy of eutherian reproduction and metabolism. Oikos 121, 102–115 (2011).
21. International HapMap 3 Consortium et al. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52–58 (2010).
22. Gayà-Vidal, M. & Albà, M. M. Uncovering adaptive evolution in the human lineage. BMC Genomics 15, 599 (2014).
23. Plunkett, J. et al. An evolutionary genomic approach to identify genes involved in human birth timing. PLoS Genet. 7, e1001365 (2011).
24. Capra, J. A., Williams, A. G. & Pollard, K. S. ProteinHistorian: tools for the comparative analysis of eukaryote protein origin. PLoS Comput. Biol. 8, e1002567 (2012).
25. Li, H. et al. TreeFam: a curated database of phylogenetic trees of animal gene families.
Nucleic Acids Res. 34, D572–80 (2006).
26. Amberger, J. S., Bocchini, C. A., Schiettecatte, F., Scott, A. F. & Hamosh, A. OMIM.org:
Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 43, D789–98 (2015).
27. Uhlén, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
28. Barrett, T. et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res. 41, D991–5 (2013).
29. Zhang, G. et al. Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. N. Engl. J. Med. 377, 1156–1167 (2017).
30. Tan, Q. et al. Epigenetic signature of preterm birth in adult twins. Clin. Epigenetics 10, 87 (2018).
31. Lizio, M. et al. Gateways to the FANTOM5 promoter level mammalian expression atlas.
Genome Biol. 16, 22 (2015).
32. Hubley, R. et al. The Dfam database of repetitive DNA families. Nucleic Acids Res. 44, D81–9 (2016).
33. Cockerham, C. C. & Weir, B. S. Covariances of relatives stemming from a population undergoing mixed self and random mating. Biometrics 40, 157–164 (1984).
34. 1000 Genomes Project Consortium et al. A global reference for human genetic variation.
Nature 526, 68–74 (2015).
35. MacArthur, J. et al. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res. 45, D896–D901 (2017).
36. Denny, J. C. et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat. Biotechnol. 31, 1102–
1110 (2013).
37. Carithers, L. J. et al. A Novel Approach to High-Quality Postmortem Tissue Procurement:
The GTEx Project. Biopreserv. Biobank. 13, 311–319 (2015).
38. Danecek, P. et al. The variant call format and VCFtools. Bioinformatics 27, 2156–2158 (2011).
39. Mungall, C. J., Emmert, D. B. & FlyBase Consortium. A Chado case study: an ontology- based modular schema for representing genome-associated biological information.
Bioinformatics 23, i337–46 (2007).